Rates of some estrogen-associated diseases, such a breast cancer and hip fracture, are lower in regions where diets high in phytoestrogens are consumed. Thus, phytoestrogens may be estrogen antagonists (cancer prevention) or relative agonists (fracture prevention). This is consistent with in-vitro studies: phytoestrogens vary in estrogenicity. Phytoestrogens may also work through non-estrogen pathways. Observational studies that have measured phytoestrogen exposures (dietary or serum) and related these to outcomes are scant. This paucity of studies is due to the challenges inherent in studying phytoestrogen consumption in free-living populations, including: 1) limited access to persons with diets rich in phyto-nutrients; 2) assessing nutrient values of mixed dishes, which characterize phytoestrogen-rich diets, is complex; 3) databases to compute phytoestrogen nutrient values are limited; and 4) accounting for phytoestrogen metabolic capability is difficult. We propose an observational study of the relations between both dietary & serum measures of phytoestrogens and phytoestrogen metabolites and 4 outcomes: bone mineral density (BMD), vasomotor symptoms (VMS), urinary incontinence (UI) and cognitive performance. A strength of our study is that it will address each of the 4 challenges described above (detailed within). The current study will make use of exposure and outcomes data collected for over 10 years as part of the Study of Women's Health Across the Nation (SWAN). SWAN is a large multi-ethnic cohort of mid-life US women. SWAN has already obtained specially modified food frequency questionnaires (FFQs) at 3 time points; the current project will greatly expand the phytoestrogen nutrient database and will estimate phytoestrogen intakes from these FFQs. We also propose to also analyze stored serum samples from 2 of the SWAN sites (in California), chosen because they house Caucasian, Japanese, and Chinese participants. Stored serum, from the 3 same time points as the FFQs, will be assayed for selected isoflavones & metabolites. We will conduct analyses to address the following major questions: Is dietary phytoestrogen exposure associated with BMD, VMS, UI, or cognitive performance over time? Does the effect of dietary phytoestrogens on these outcomes vary depending on menopause transition (MT) stage? In the California sub-sample, we will examine whether serum levels of isoflavones & isoflavone metabolites are related to the same 4 outcomes and whether the relation depends on MT stage. In the California sub-sample, we have the unique opportunity to determine whether the presence of isoflavone metabolites amplifies the effects of the dietary or serum isoflavones. PUBLIC HEALTH RELEVANCE: We propose an observational study of the relations between plant estrogen consumption and 4 outcomes that are important to the health of women: bone density, hot flashes, urinary incontinence and cognitive performance. This study will serve as a translational research step, either encouraging or dissuading the future development of plant estrogen-based interventions for the treatment of conditions (e.g., hot flashes) or the maintenance of health (e.g., bone density preservation). [unreadable] [unreadable] [unreadable]